Obesity is a leading cause of morbidity and mortality worldwide, and wasting is a dread complication of common diseases such as cancer. As there are no highly effective medical treatments for either condition, elucidating the mechanisms that govern food intake and body weight is a high priority. Major insights have been gained regarding the processes that govern long-term energy homeostasis, as well as those that signal post-prandial satiety and terminate individual meals. In contrast, the factor(s) that mediate the powerful sensation of pre-prandial hunger and initiate meals remain largely unknown. The novel hormone ghrelin is a reasonable candidate for a physiological meal initiator. It is secreted by the stomach, circulates in blood, and powerfully and rapidly increases food intake in rodents. We have shown that plasma levels dramatically rise and fall shortly before and after every meal in humans. Other observations suggest that ghrelin may also participate in long-term energy homeostasis. Chronic administration increases body weight, blockade of basal levels decreases food intake, and ghrelin levels increase with acute or chronic energy deficit, consistent with an adaptive response. We propose to address the following questions. (1) Is ghrelin a physiological meal initiator? We will determine if plasma ghrelin surges predict voluntarily initiated meals in humans isolated from external meal cues. In rats we will evaluate whether physiological doses of ghrelin initiate meals, and if chronic blockade of endogenous ghrelin signaling disrupts meal initiation. (2) Does ghrelin regulate long-term energy homeostasis? In order to assess whether ghrelin participates in the adaptive response to an energy deficit, we will evaluate the effect of both fasting and diet-induced weight loss on human plasma ghrelin levels. In rats we will determine if a ghrelin antagonist blunts the adaptive hyperphagic and hypothalamic neuroendocrine responses to fasting, ameliorates the obesity phenotype of leptin deficiency, or causes weight loss in normal animals. 3) What regulates ghrelin expression? Extending our finding of meal-related ghrelin suppression in humans, we will determine in humans and rats the relative contributions to circulating ghrelin levels of enteral vs. parenteral nutrients, gastric distension, specific classes of macronutrients, leptin, fasting, and other meal-regulated gut peptides. 4) Is ghrelin effective as a drug to treat cancer anorexia in a rat model?